The Optimal Corepressor Function of Nuclear Receptor Corepressor (NCoR) for Peroxisome Proliferator-activated Receptor γ Requires G Protein Pathway Suppressor 2

Guo, Chun; Li, Yali; Gow, Chien‐Hung; Wong, May Q.; Zha, Jikun; Yan, Cheng; Liu, Hongqi; Wang, Yongjun; Burris, Thomas P.; Zhang, Jinsong

doi:10.1074/jbc.m114.598797

Cited by 23 publications

(27 citation statements)

References 76 publications

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“…Elevations in PPARg, SMRT, and NCOR which all interact to control downstream adipocyte fate and function, glucose handling, insulin sensitivity, mitochondrial oxidative capacity, and thermogenesis, were also found. [43,49] [36,50] [33] [51][52][53]. Thus, as inferred from the calorimetry data, there is upregulation of transcriptional machinery capable of increasing energy production and glucose utilization within the VAT of SG mice.…”

Section: Discussionmentioning

confidence: 99%

“…There was contribution from silencing mediator of retinoid and thyroid hormone receptors (SMRT) and nuclear receptor co-repressor (NCOR), which through subdomains, effect PPARy signaling and modulate the immune response by transrepression of co-activators of NF-kB, IRFs and LPS targets. [33][34][35][36] Finally, there was expression mapping to other transcription factors such as Interferon-regulatory factor 8 (IRF8), MDS1 and EVI1 Complex Locus (MECOM), Polycomb Repressive Complex 2 Subunit (SUZ12), and E2A immunoglobulin enhancer-binding factor E12/E47 (E2A), which have roles in determining immune cell fate, cell resource utilization, and/or other metabolic processes.…”

Section: Rna Sequencing Reveals Gene Level Changes In Visceral Fat Immentioning

confidence: 99%

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Sleeve Gastrectomy enhances glucose utilization and remodels adipose tissue independent of weight loss

Harris

Mina

Čabarkapa

et al. 2019

Preprint

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Objective: Sleeve gastrectomy (SG) induces weight-loss independent improvements in glucose homeostasis by unknown mechanisms. We sought to identify the metabolic adaptations responsible for these improvements.Methods: Non-obese C57Bl6/J mice on standard chow underwent SG or sham surgery. Functional testing and indirect calorimetry were used to capture metabolic phenotypes. Tissuespecific glucose uptake was assessed by 18-FDG PET/CT and RNA sequencing was used for gene expression analysis.Results: In this model, SG induced durable improvements in glucose tolerance despite not causing lasting changes in weight, fat/lean mass, or food intake. Indirect calorimetry revealed post-SG animals had respiratory exchange ratios (RER) nearing 1.0 on average and had daily RER excursions above 1.0, indicating preferential glucose utilization and increased energy demand, respectively. Sham operated mice demonstrate normal RER feeding/fasting excursions. PET/CT showed increased avidity within white adipose depots. Finally, SG led to an upregulation in the transcriptional pathways involved in energy metabolism, adipocyte maturation, and adaptive and innate immune cell chemotaxis and differentiation within the visceral adipose tissue.Conclusions: SG induces a rapid, weight-loss independent shift towards glucose utilization and transcriptional remodeling of metabolic and immune pathways in visceral adipose tissue.

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Section: Discussionmentioning

confidence: 99%

Section: Rna Sequencing Reveals Gene Level Changes In Visceral Fat Immentioning

confidence: 99%

Sleeve Gastrectomy enhances glucose utilization and remodels adipose tissue independent of weight loss

Harris

Mina

Čabarkapa

et al. 2019

Preprint

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“…Lastly, it is worth noting that there is a large body of work describing GPS2 as a transcriptional cofactor, involved in mediating both gene repression, as part of the NCoR/SMRT complex, and activation through direct interaction with nuclear receptors and other TFs [31], [37], [39], [41], [42], [76]. For example, in the adipose tissue, downregulation of GPS2 was associated with the derepression of inflammatory target genes in human obese patients [32] and with the activation of key enzymes for triglyceride breakdown, HSL and ATGL, in murine differentiating adipocytes [34].…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies by our lab and others indicate that GPS2 plays an important anti-inflammatory role in adipose tissue and macrophages and is required for the expression of genes regulating cholesterol and triglyceride metabolism [29], [31], [32], [33], [34]. Due to multiple functional interactions existing between GPS2 and various transcriptional regulators, GPS2 activity has been studied mainly in the context of its nuclear functions, including both transcriptional repression and activation [29], [31], [32], [34], [35], [36], [37], [38], [39], [40], [41], [42]. However, GPS2 also plays an important non-transcriptional role in the cytosol by regulating JNK activation downstream of TNFR1 [29].…”

Section: Introductionmentioning

confidence: 99%

Systemic insulin sensitivity is regulated by GPS2 inhibition of AKT ubiquitination and activation in adipose tissue

Cederquist

Lentucci

Martinez-Calejman

et al. 2017

Molecular Metabolism

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ObjectiveInsulin signaling plays a unique role in the regulation of energy homeostasis and the impairment of insulin action is associated with altered lipid metabolism, obesity, and Type 2 Diabetes. The main aim of this study was to provide further insight into the regulatory mechanisms governing the insulin signaling pathway by investigating the role of non-proteolytic ubiquitination in insulin-mediated activation of AKT.MethodsThe molecular mechanism of AKT regulation through ubiquitination is first dissected in vitro in 3T3-L1 preadipocytes and then validated in vivo using mice with adipo-specific deletion of GPS2, an endogenous inhibitor of Ubc13 activity (GPS2-AKO mice).ResultsOur results indicate that K63 ubiquitination is a critical component of AKT activation in the insulin signaling pathway and that counter-regulation of this step is provided by GPS2 preventing AKT ubiquitination through inhibition of Ubc13 enzymatic activity. Removal of this negative checkpoint, through GPS2 downregulation or genetic deletion, results in sustained activation of insulin signaling both in vitro and in vivo. As a result, the balance between lipid accumulation and utilization is shifted toward storage in the adipose tissue and GPS2-AKO mice become obese under normal laboratory chow diet. However, the adipose tissue of GPS2-AKO mice is not inflamed, the levels of circulating adiponectin are elevated, and systemic insulin sensitivity is overall improved.ConclusionsOur findings characterize a novel layer of regulation of the insulin signaling pathway based on non-proteolytic ubiquitination of AKT and define GPS2 as a previously unrecognized component of the insulin signaling cascade. In accordance with this role, we have shown that GPS2 presence in adipocytes modulates systemic metabolism by restricting the activation of insulin signaling during the fasted state, whereas in absence of GPS2, the adipose tissue is more efficient at lipid storage, and obesity becomes uncoupled from inflammation and insulin resistance.

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“…Even though mitochondria are semi-independent organelles containing multiple copies of their own genome, most of the mitochondrial proteome is encoded by nuclear genes and, thus, regulated by nuclear transcription factors (TFs) and associated cofactors including PGC1α, NRF1, GABPα, ATF5, ERRα and others (Brenmoehl and Hoeflich, 2013;Fiorese et al, 2016;Hock and Kralli, 2009;Scarpulla et al, 2012;Whelan and Zuckerbraun, 2013;Wu et al, 1999). Thus, the biogenesis of mitochondria and the maintenance of mitochondrial homeostasis critically depend on nuclear transcription and through protein stabilization/degradation (Huang et al, 2015) and GPS2 deficiency in mice is embryonic lethal (Guo et al, 2014), indicating the physiological importance of GPS2. Previous work from us and other laboratories indicate that nuclear GPS2 acts as a transcriptional cofactor playing a dual role as corepressor and coactivator for a number of transcription factors Cheng and Kao, 2009;Guo et al, 2014;Jakobsson et al, 2009;Peng et al, 2001;Venteclef et al, 2010;Zhang et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

GPS2 regulates mitochondria biogenesis via mitochondrial retrograde signaling and chromatin remodeling of nuclear-encoded mitochondrial genes

Cardamone

Tanasă

Cederquist

et al. 2017

Preprint

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2 SummaryAs most of the mitochondrial proteome is encoded in the nucleus, mitochondrial functions critically depend on nuclear gene expression and bidirectional mito-nuclear communication. However, mitochondria-to-nucleus communication pathways are incompletely understood. Here, we identify G-Protein Pathway Suppressor 2 (GPS2) as a mediator of mitochondrial retrograde signaling and a key transcriptional activator of nuclear-encoded mitochondrial genes in mammals. GPS2 regulated translocation from mitochondria to nucleus is essential for the transcriptional activation of the nuclear stress response to mitochondrial depolarization and for supporting basal mitochondrial biogenesis in differentiating adipocytes and in brown adipose tissue from mice. In the nucleus, GPS2 recruitment to target gene promoters regulates histone H3K9 demethylation and RNA Polymerase II (POL2) activation through inhibition of Ubc13-mediated ubiquitination. Together, these findings reveal an unexpected layer of regulation of mitochondrial gene transcription as they uncover a novel mitochondrianuclear communication pathway.

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The Optimal Corepressor Function of Nuclear Receptor Corepressor (NCoR) for Peroxisome Proliferator-activated Receptor γ Requires G Protein Pathway Suppressor 2

Cited by 23 publications

References 76 publications

Sleeve Gastrectomy enhances glucose utilization and remodels adipose tissue independent of weight loss

Sleeve Gastrectomy enhances glucose utilization and remodels adipose tissue independent of weight loss

Systemic insulin sensitivity is regulated by GPS2 inhibition of AKT ubiquitination and activation in adipose tissue

GPS2 regulates mitochondria biogenesis via mitochondrial retrograde signaling and chromatin remodeling of nuclear-encoded mitochondrial genes

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